Epothilones are macrocyclic lactones with useful antifungal and cytotoxic properties. Their action is based on stabilization of microtubules, causing mitotic arrest in rapidly dividing cells and thus inhibition of the growth of tumors. For reviews, see E. Nogales, Ann. Rev. Biochem., 2000, 69:277–302; L. Wessjohann, Angew. Chem. Int. Ed. Engl. 1997, 36:715–718; Höfle et al., Angew. Chem. Int. Ed. Engl., 1996, 35:1567–1569; and K. C. Nicolaou et al., Angew. Chem. Intl. Ed. Engl., 1998, 37:2014–2045.
Among the numerous semi-synthetic derivatives of epothilone that have been reported, C-21 modified epothilones, and their derivatives, are particularly promising anti-tumor agents. C-21 modified epothilones are disclosed in U.S. Pat. No. 6,262,094; issued Jul. 17, 2000. The preparation of C-21 modified epothilones has been described by Höfle et al. in German applications DE 199 07 588 and DE 199 30 111, and in PCT international application WO 00/50423. Methods of preparing 21-amino epothilone derivatives are also described in U.S. provisional application Ser. No. 60/357,554; filed Feb. 15, 2002.
C-21 modified epothilones, however, are not readily compounded into suitable formulations for administration. They possess low solubility in water, degrade in contact with aqueous media, are sensitive to low pH when in solution, are light sensitive, are “Class D” cytotoxic and have poor wetting characteristics. Although one or two of these characteristics might be compensated for in compounding a pharmaceutical formulation for parenteral administration, the combination of all of these properties has until now presented a formidable challenge.
There remains a need for formulations of C-21 modified epothilone derivatives that are stable and easily prepared for administration in a safe and convenient manner. The present invention describes formulations whereby the epothilone analogs described above can be safely dispensed and administered via injection, without appreciable loss of potency.
Furthermore, many anti-cancer drugs have toxicity concerns. Indeed, the therapeutic profile of many potent antitumor drugs is poor as a result of toxicity. Therefore, there is also a need for methods of administration and dosing schedules that reduce or avoid the toxicity associated with antitumor agents. The methods can allow exploitation of potent antitumor agents that would otherwise not be used clinically.